Shared and unique 3D genomic features of substance use disorders across multiple cell types
Khanh B Trang1,2, Alessandra Chesi1,3, Sylvanus Toikumo4,5
1Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Medrxiv : the Preprint Server for Health Sciences
|July 29, 2024
Summary
Genetic studies reveal shared risk for substance use disorders across brain and pancreatic cells. This research highlights specific cell types, like cortical neurons and beta cells, crucial for understanding these complex conditions.
Area of Science:
- Genomics
- Neuroscience
- Endocrinology
Background:
- Genome-wide association studies (GWAS) indicate shared genetic factors across alcohol, opioid, tobacco, and cannabis use disorders.
- The precise causal variants, effector genes, and cellular contexts underlying these shared genetic components remain largely unknown.
Purpose of the Study:
- To identify specific cell types and genomic regions associated with heritability of substance use disorders.
- To investigate the genetic overlap between substance use disorders and metabolic diseases, such as Type 2 Diabetes (T2D).
Main Methods:
- Integration of 3D genomics data (Capture-C/Hi-C, ATAC-seq, RNA-seq) across diverse human cell types with GWAS summary statistics.
- Application of stratified LD regression to assess SNP heritability enrichment in various cell types for alcohol use disorder (AUD), tobacco use disorder (TUD), opioid use disorder (OUD), and cannabis use disorder (CanUD).
- Analysis of genetic correlations between substance use disorders and T2D, particularly within pancreatic beta cells.
Main Results:
- Significant heritability enrichments (P<0.05) were found in 14 cell types, with iPSC-derived cortical neurons and neural progenitors showing up to 9.2-fold enrichment.
- Pancreatic cell types, including beta cells, exhibited up to 4.8-fold heritability enrichment for TUD, suggesting a link with metabolic processes.
- Significant positive genetic correlations were observed between T2D and TUD/CanUD, and a negative correlation with AUD. The T2D-TUD correlation was stronger in pancreatic beta cells.
Conclusions:
- The study implicates specific neuronal cell types in the genetic architecture of multiple substance use disorders.
- A surprising genetic overlap between TUD/CanUD and T2D, particularly in pancreatic beta cells, suggests shared biological pathways.
- These findings provide crucial cellular context for future functional studies aimed at uncovering causal mechanisms of substance use disorders.
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